Global warming and air pollution affect the transmission pathway and the survival of viruses, altering the human immune system as well. The first wave of the COVID-19 pandemic dramatically highlights ...the key roles of climate and air chemistry in viral epidemics. The elongated form of the Italian peninsula and the two major islands (the largest in Europe) is a perfect case study to assess some of these key roles, as the fate of the virus is mirroring the industrialization in the continental part of our country. Fine particulate matter (PM
2.5
), geography, and climate explain what is happening in Italy and support cleaner air actions to address efficiently other outbreaks. Besides the environmental factors, future works should also address the genetic difference among individuals to explain the spatial variability of the human response to viral infections.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The most significant genetic influence on eye color pigmentation is attributed to the intronic SNP rs12913832 in the HERC2 gene, which interacts with the promoter region of the contiguous OCA2 gene. ...This interaction, through the formation of a chromatin loop, modulates the transcriptional activity of OCA2, directly affecting eye color pigmentation. Recent advancements in technology have elucidated the precise spatial organization of the genome within the cell nucleus, with chromatin architecture playing a pivotal role in regulating various genome functions. In this study, we investigated the organization of the chromatin close to the HERC2/OCA2 locus in human lymphocyte nuclei using fluorescence in situ hybridization (FISH) and high-throughput chromosome conformation capture (Hi-C) data. The 3 Mb of genomic DNA that belonged to the chromosomal region 15q12-q13.1 revealed the presence of three contiguous chromatin loops, which exhibited a different level of compaction depending on the presence of the A or G allele in the SNP rs12913832. Moreover, the analysis of the genomic organization of the genes has demonstrated that this chromosomal region is evolutionarily highly conserved, as evidenced by the analysis of syntenic regions in species from other Vertebrate classes. Thus, the role of rs12913832 variant is relevant not only in determining the transcriptional activation of the OCA2 gene but also in the chromatin compaction of a larger region, underscoring the critical role of chromatin organization in the proper regulation of the involved genes. It is crucial to consider the broader implications of this finding, especially regarding the potential regulatory role of similar polymorphisms located within intronic regions, which do not influence the same gene by modulating the splicing process, but they regulate the expression of adjacent genes. Therefore, caution should be exercised when utilizing whole-exome sequencing for diagnostic purposes, as intron sequences may provide valuable gene regulation information on the region where they reside. Thus, future research efforts should also be directed towards gaining a deeper understanding of the precise mechanisms underlying the role and mode of action of intronic SNPs in chromatin loop organization and transcriptional regulation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Age-related disorders, such as Alzheimer's disease (AD) and age-related macular degeneration (AMD) share common features such as amyloid-β (Aβ) protein accumulation. Retinal deposition of Aβ ...aggregates in AMD patients has suggested a potential link between AMD and AD. In the present study, we analyzed the expression pattern of a focused set of miRNAs, previously found to be involved in both AD and AMD, in the retina of a triple transgenic mouse model of AD (3xTg-AD) at different time-points. Several miRNAs were differentially expressed in the retina of 3xTg-AD mice, compared to the retina of age-matched wild-type (WT) mice. In particular, bioinformatic analysis revealed that miR-155 had a central role in miRNA-gene network stability, regulating several pathways, including apoptotic and inflammatory signaling pathways modulated by TNF-related apoptosis-inducing ligand (TNFSF10). We showed that chronic treatment of 3xTg-AD mice with an anti-TNFSF10 monoclonal antibody was able to inhibit the retinal expression of miR-155, which inversely correlated with the expression of its molecular target SOCS-1. Moreover, the fine-tuned mechanism related to TNFSF10 immunoneutralization was tightly linked to modulation of TNFSF10 itself and its death receptor TNFRSF10B, along with cytokine production by microglia, reactive gliosis, and specific AD-related neuropathological hallmarks (i.e., Aβ deposition and Tau phosphorylation) in the retina of 3xTg-AD mice. In conclusion, immunoneutralization of TNFSF10 significantly preserved the retinal tissue in 3xTg-AD mice, suggesting its potential therapeutic application in retinal degenerative disorders.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of complex etiology leading to motor neuron degeneration. Many gene alterations cause this pathology, including mutation ...in Cu, Zn superoxide dismutase (SOD1), which leads to its gain of function. Mutant SOD1 proteins are prone to aberrant misfolding and create aggregates that impair autophagy. The hypoxic stress is strictly linked to the disease progression since it induces uncontrolled autophagy activation and the consequent high rates of cell death. Previously, we showed that pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activity in cultured mSOD1 motor neurons exposed to serum deprivation. To date, no studies have examined whether the protective effect of PACAP on mSOD1 cells exposed to hypoxic insult is mediated through the regulation of the autophagy process. In the present study, we used the neuroblastoma-spinal cord-34 (NSC-34) cell line, stably expressing human wild type or mutant SOD1 G93A, to represent a well characterized in vitro model of a familial form of ALS. These cells were exposed to 100-µM desferrioxamine mesylate salt for 24h, to mimic the hypoxic stress affecting motor neurons during the disease progression. Our results showed that PACAP treatment significantly reduced cell death and hypoxia-induced mSOD1 accumulation by modulating the autophagy process in G93A motor neurons, as revealed by the decreased LC3II and the increased p62 levels, two autophagy indicators. These results were also confirmed by evaluating the vacuole formation detected through light chain 3 (LC3) immunofluorescence. Furthermore, the PACAP effects on autophagy seem to be mediated through the activation of the MAPK/ERK signaling pathway. Overall, our data demonstrated that PACAP exerts an ameliorative effect on the mSOD1 motor neuron viability by modulating a hypoxia-induced autophagy process through activation of MAPK/ERK signaling cascade.
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Abstract E3 ubiquitin protein ligase encoded by ARIH2 gene catalyses the ubiquitination of target proteins and plays a crucial role in posttranslational modifications across various cellular ...processes. As prior documented, mutations in genes involved in the ubiquitination process are often associated with autism spectrum disorder (ASD) and/or intellectual disability (ID). In the current study, a de novo heterozygous mutation was identified in the splicing intronic region adjacent to the last exon of the ARIH2 gene using whole exome sequencing (WES). We hypothesize that this mutation, found in an ASD/ID patient, disrupts the protein Ariadne domain which is involved in the autoinhibition of ARIH2 enzyme. Predictive analyses elucidated the implications of the novel mutation in the splicing process and confirmed its autosomal dominant inheritance model. Nevertheless, we cannot exclude the possibility that other genetic factors, undetectable by WES, such as mutations in non-coding regions and polygenic risk in inter-allelic complementation, may contribute to the patient's phenotype. This work aims to suggest potential relationship between the detected mutation in ARIH2 gene and both ASD and ID, even though functional studies combined with new sequencing approaches will be necessary to validate this hypothesis.
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Chromosomal rearrangements have been shown to alter genome organization, consequently having an impact on gene expression. Studies on certain types of leukemia have shown that gene expression can be ...exacerbated by the altered nuclear positioning of fusion genes arising from chromosomal translocations. However, studies on lymphoma have been, so far, very limited. The scope of this study was to explore genome organization in lymphoma cells carrying the t(14;18)(q32;q21) rearrangement known to results in over-expression of the
gene. In order to achieve this aim, we used fluorescence in situ hybridization to carefully map the positioning of whole chromosome territories and individual genes involved in translocation in the lymphoma-derived cell line Pfeiffer. Our data show that, although there is no obvious alteration in the positioning of the whole chromosome territories, the translocated genes may take the nuclear positioning of either of the wild-type genes. Furthermore, the
gene was looping out in a proportion of nuclei with the t(14;18) translocation but not in control nuclei without the translocation, indicating that chromosome looping may be an essential mechanism for
expression in lymphoma cells.
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Activity-dependent neuroprotective protein (ADNP) is a neuroprotective protein essential for embryonic development, proper brain development, and neuronal plasticity. Its mutation causes the ...autism-like ADNP syndrome (also called the Helsmoortel-Van der Aa syndrome), characterized by neural developmental disorders and motor dysfunctions. Similar to the ADNP syndrome, the
haploinsufficient mouse shows low synapse density, leading to motor and cognitive ability delays. Moderate physical activity (PA) has several neuroprotective and cognitive benefits, promoting neuronal survival, differentiation, neurogenesis, and plasticity. Until now, no study has investigated the effect of moderate exercise on ADNP expression and distribution in the rat brain. The aim of the current investigation was to study the effects of moderate exercise on the ADNP expression and neuronal activation measured by the microtubule protein β-Tubulin III. In pursuit of this objective, twenty-four rats were selected and evenly distributed into two categories: sedentary control rats and rats exposed to moderate physical activity on a treadmill over a span of 12 weeks. Our results showed that moderate PA increases the expression of ADNP and β-Tubulin III in the dentate gyrus (DG) hippocampal region and cerebellum. Moreover, we found a co-localization of ADNP and β-Tubulin III in both DG and cerebellum, suggesting a direct association of ADNP with adult neuronal activation induced by moderate PA.
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Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment ...often related to both underlying genetic etiology and abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us to sequence large portions of DNA quickly and with low costs. The aim of this study is to evaluate the use of whole-exome sequencing (WES) as a first-line molecular genetic test in a sample of subjects with DEEs characterized by early-onset drug-resistant epilepsies, associated with global developmental delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants with a detection rate of 43%. The identified variants were highlighted on 29 different genes including, 3 new candidate genes (
,
,
) for DEEs never identified before. In total, 23 out of 35 (66%) de novo variants were identified. The most frequently identified type of inheritance was autosomal dominant de novo (60%) followed by autosomal recessive in homozygosity (17%) and heterozygosity (11%), autosomal dominant inherited from parental mosaicism (6%) and X-linked dominant de novo (6%). The most frequent mutations identified were missense (75%) followed by frameshift deletions (16%), frameshift duplications (5%), and splicing mutations (3%). Considering the results obtained in the present study we support the use of WES as a form of first-line molecular genetic testing in DEEs.
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A characteristic hallmark of Alzheimer’s disease (AD) is the intracellular accumulation of hyperphosphorylated tau protein, a phenomenon that appears to have associations with oxidative stress, ...double-stranded DNA breakage, and the de-condensation of heterochromatin. Re-entry into the cell division cycle appears to be involved in the onset of this neurodegenerative process. Indeed, the cell cycle cannot proceed regularly in the differentiated neurons leading to cell death. Here, we induced cell cycle reactivation in neuronal-like cells, obtained by neuroblastoma cells treated with retinoic acid, by exposure to forskolin or aniline. These compounds determine tau hyperphosphorylation or oxidative stress, respectively, resulting in the appearance of features resembling the start of neuronal degeneration typical of AD, such as tau hyperphosphorylation and re-entry into the cell cycle. Indeed, we detected an increased transcriptional level of cyclins and the appearance of a high number of mitotic cells. We also observed a delay in the initiation of the cell cycle when forskolin was co-administered with pituitary adenylate cyclase-activating polypeptide (PACAP). This delay was not observed when PACAP was co-administered with aniline. Our data demonstrate the relevance of tau hyperphosphorylation in initiating an ectopic cell cycle in differentiated neuronal cells, a condition that can lead to neurodegeneration. Moreover, we highlight the utility of neuroblastoma cell lines as an in vitro cellular model to test the possible neuroprotective effects of natural molecules.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In recent decades, the use of genetic polymorphisms related to specific phenotypes, such as eye color, has greatly contributed to the development of the research field called forensic DNA phenotyping ...(FDP), enabling the investigators of crime cases to reduce the number of suspects, making their work faster and more precise. Eye color is a polygenic phenotype, and many genetic variants have been highlighted, with the major contributor being the HERC2-OCA2 locus, where many single nucleotide variations (SNPs) were identified. Interestingly, the HERC2-OCA2 locus, containing the intronic SNP rs12913832, the major eye color determinant, shows a high level of evolutionary conservation across many species of vertebrates. Currently, there are some genetic panels to predict eye color by genomic DNA analysis, even if the exact role of the SNP variants in the formation of eye color is still poorly understood, with a low level of predictivity in the so-called intermediate eye color. Many variants in OCA2, HERC2, and other genes lie in introns or correspond to synonymous variants, highlighting greater complexity in the mechanism of action of such genes than a simple missense variation. Here, we show the main genes involved in oculocutaneous pigmentation and their structural and functional features, as well as which genetic variants show the highest level of eye color predictivity in currently used FDP assays. Despite the great recent advances and impact of FDP in criminal cases, it is necessary to enhance scientific research to better understand the mechanism of action behind each genetic variant involved in eye color, with the goal of obtaining higher levels of prediction.